1. Field of the Invention
The present invention is related to medical treatments involving the human brain and, more specifically without limitation, to real-time automated sensing and contingent, or closed-loop prevention/control or blockage of brain state changes using at least electrical or thermal signals either individually or simultaneously for detection or prediction of seizures or sensing of other changes in brain states; automated timely and safe delivery of cryogenic or other therapies; quantitative assessment of their efficacy and safety; and means for optimization thereof.
2. Discussion of the Related Art
Neuronal and, by extension, brain metabolic and electrical activity of poikilothermic and homeothermic animals are without exception temperature-dependent. Low temperatures (below 35° C.) in homeotherms, and more specifically in humans, have an easily discernible effect on behavior and on an EEG, which is a reliable index of cortical electrical activity. At such temperatures, cerebral blood flow, oxygen and glucose consumption become depressed and, due to tight electro-metabolic coupling, so does neuronal function and its by-product, electrical activity. Brain cooling has a protective effect on the integrity of its tissue, a feature that has its own therapeutic applications.
For example, hypothermia minimizes damage in models of brain ischemia by decreasing both the metabolic demand of the brain tissue and the production of glutamate and dopamine, which under certain conditions can be excito-toxic. These effects make hypothermia well-suited for the treatment of neurological diseases that are characterized by the following:                1) absolute or relative, global or local neuronal hyper excitability, such as in epilepsy;        2) an imbalance in the degree of neuronal activity between/among structures which form part of a functional network, such as in Parkinson's disease;        3) reduction in the supply of energy substrates, such as in stroke; and        4) activation/release of pathoclitic enzymes, such as in trauma, stroke, infection or prolonged/frequent seizures (status epilepticus).        
Cooling can also be used for functional cortical localization or assessment of cognitive functions to assist in neurosurgical planning. Cryogenics has definite important advantages over electrical stimulation, the current standard for cortical localization, as follows:                a) cooling, unlike electrical stimulation (ES), does not precipitate seizures; and        b) unlike ES, which requires at least two stimulating electrodes and which has the potential to reach all structures between the electrodes and even those remote to them via existing neural pathways, the effects of cooling remain more localized and are more gradual than ES, thus providing more selective and interpretable information and also a higher therapeutic index.        
Although cooling of brain tissue has been an object of several prior art approaches for various medical treatments, most of those approaches have been limited to cooling the most superficial layers of small cortical areas or in some cases just the scalp. Some other prior art approaches utilize cryogenic energy to ablate or destroy brain tissue. Cooling for the sole purpose of tissue ablation/destruction requires processing of very few, if any, input signals and parameter controls whereas reversible safe cooling of brain tissue for control of state changes such as seizure blockage, as taught by the present disclosure for seizure blockage purposes, is a highly time-sensitive task. For example, while methods for measuring tissue properties, such as thermal conductivity for the purpose of controlling the extent and degree of freezing, which is an irreversible destructive procedure, are disclosed in U.S. Pat. No. 6,190,378, that procedure is neither time-sensitive nor dependent on the sensing of changes in electrical or thermal signals as required for seizure blockage using reversible cooling. No prior art reference appears to disclose seizure blockage as taught herein; references that border on such an application appear to have very limited usefulness or relevance for the medical applications disclosed herein. One prior art reference discloses means to block seizures through reversible cooling, namely U.S. Pat. No. 6,248,126 to Lesser et al, but has significant limitations, which make it highly unlikely that seizures can be blocked using such a device, even if the seizures originate from exposed gyri, designated by numeral 4 in FIG. 1, for the following reasons:
1) placement of the device of the '126 patent over the most superficial cortical layer of exposed gyri as taught by the '126 patent prevents timely cooling of deeper cortical layers (IV-VI) from where most seizures originate because (a) there are no means for attachment and, as a result, the cooling device floats over the cerebrospinal fluid and the fluid currents, through convection, carry cooling energy away from the target site thereby slowing down the rate at which tissue cooling can occur at the most superficial cortical layers; and (b) thermal diffusivity of brain tissue is such that rapid or timely cooling of deeper layers to block seizures can not take place; and
2) the majority of cortical gyri are not exposed, designated by numeral 5 in FIG. 1, and thus are not amenable to cooling using such a device.
Epilepsy affects about 2.7 million people in the United States and about 60 million worldwide. Approximately 30% of this population has pharmaco-resistant epilepsy, defined as at least one monthly seizure despite treatment with appropriate drugs at therapeutic concentrations. New therapies, which are both safe and effective, are required, given the existent, unmet need. Cooling of brain tissue is one such therapy with great potential as its effects are fully reversible and safe since the range of effective temperatures has no adverse effects on tissue viability or integrity and it is not known to precipitate or worsen seizures. While as early as 1974, it was shown that lowering the temperature of the midbrain prevents epileptiform activity, this therapeutic modality has received little attention due mainly to lack of suitable implantable devices and of interest in therapies other than pharmacological ones. Newly published evidence lends more support for an anti-seizure role for cooling of brain tissue. For example, U.S. Pat. No. 6,248,126 to Lesser et al discloses the use of a device based on the Peltier effect for cooling small areas of the cortical surface for seizure control. That device has important practical limitations, as described below, which translate into reduced efficacy and applicability. For example, that device does not provide a means to transfer heat (or cooling) in a timely manner from the surface to deeper neocortical regions from where seizures originate, which considerably limits efficacy since the delay in delivering therapy to critical regions allows the seizure to spread and gain intensity. This delay is explained by the fact that temperature gradients are steep and limit cooling to the immediate vicinity of the device, which necessitates that the cooling source be located as close to the target as possible for the therapy to be effective. Thermal diffusivity brain models reveal that lowering the temperature of a region located 5 mm from the cooling source, which is the average width of the cortex, from 37° C. to 16° C. takes approximately thirty seconds. Since placement of a Peltier device as taught by Lesser et al is on the cortical surface and the distance between that Peltier device and the seizure-generating cortical layers is about 5 mm, it is highly unlikely that they can be cooled down sufficiently timely to block seizures and prevent their spread. For any contingent therapy to be efficacious, it must reach the site of origin within five seconds of seizure onset. The ability to rapidly reach the seizure-generating tissue tissue-generating seizures (epileptogenic region) is essential for the success of cryogenic therapy. Moreover, the device and approach of the '126 patent do not have the means to monitor tissue electrical activity required to maximize efficacy, minimize the risk of freezing the tissue, assess therapeutic efficacy, and operate efficiently. Other prior art cooling catheters and probes are not suitable for use in epilepsy.
Cooling offers certain advantages over electrical stimulation for control of state changes or of cortical or subcortical functions as follows:
a) the only critical control parameter in cooling therapy is temperature as compared to intensity, frequency, pulse width, waveform, size and orientation of the field which determine efficacy and safety of electrical stimulation;
b) cooling has a greater safety margin than electrical stimulation because of the less instantaneous nature of the change in temperature particularly at the device-tissue interface, as opposed to charge deposition over the area covered by the electrical field and the known ability of electrical stimulation to induce seizures when certain parameters are utilized; and
c) cooling allows good-quality recording of electrical brain signals during cryogenic therapy for continuous real-time assessment of efficacy, an important function which can not be accomplished during delivery of electrical therapy, since electrical therapy saturates amplifiers and distorts brain electrical activity, not only for the duration of the electrical stimulation but also for a few seconds after its conclusion, which precludes meaningful analysis and valid interpretation of brain electrical signals during a certain period. However, since electrical diffusivity is much higher than thermal diffusivity, electrical therapy may have quicker effects than is realizable from cryogenic therapy.
One of the therapies used for epilepsy and other neurological disorders is drugs. Any brain-acting drug given orally or intravenously must be able to cross the blood-brain barrier. The blood brain barrier (BBB) only allows certain small lipid soluble compounds through, thus protecting the brain against certain toxic substances which circulate in the blood stream. While this is a life supporting protection for the brain, the existence of the BBB limits the amount and rate of delivery of most drugs. Direct drug or chemical delivery to brain targets (thereby bypassing the BBB) has certain advantages over the systemic and intravenous route. Direct drug delivery into brain may be achieved via conduits (macro-, micro- or nano-tubes), nanoparticles, drug carrying polymers, and drug delivery matrices. However, the chemical (mass transfer) diffusivity of the brain is low, which makes it difficult for the drugs to diffuse throughout the brain. For this reason, the drug to be used must be placed as close to the target of interest as possible and depending on the application, its diffusion rate may be enhanced using physical (i.e., ultrasound) or chemical means. The natural limitations to brain drug diffusion, are partially overcome by the current invention, which makes it possible to reach the deeper layers of the cortex and enables drugs to be delivered closer to target regions/structures, than prior art.
What is needed is a multi-purpose device, which the present invention provides for single, dual, simultaneous or sequential electrical and/or cryogenic and/or pharmacologic therapy for control of brain state changes or of cortical and subcortical functions. What is also needed is a cooling or other therapeutic device that is principally, but not only, activated in response to a cue including, but not limited to, sensing of a seizure, to thereby minimize power consumption, a prerequisite for miniaturization and implantation.